Innovative Strategies to Combat Kidney Disease

By Julius Goepp, MD

By Julius Goepp, MD

Silymarin

Silymarin is extracted from milk thistle (Silybum marianum), a plant rich in the flavonolignans silychristin, silydianin, silybin A, silybin B, isosilybin A and isosilybin B, which are collectively known as the silymarin complex.

This safe, natural compound has a long history as a traditional therapy for liver and kidney conditions.35,36 It has been used in Western medical practice for more than a quarter of a century as the treatment of choice for the serious kidney injury resulting from severe mushroom poisoning, owing to its potent antioxidant and nephron-protective effects.37 In fact, we’ve known since 1979 that kidney injury by mushroom poisoning in animals pre-treated with silymarin can be almost entirely prevented.38 These effects make it a natural choice for protection against drug-induced kidney damage, since so many drugs can act like poisons, exerting extreme oxidant stress on kidney tissue.

Mushroom poisons (mycotoxins) are among the most deadly natural toxins known. Their kidney toxicity is surpassed only by some of the most aggressive chemotherapy agents. Physicians have therefore looked to silymarin as a potential “renoprotective” agent for patients undergoing chemotherapy.

Silymarin is also protective against several classes of nephrotoxic drugs, in particular cisplatin and Adriamycin®, two of the most potent chemotherapeutic drugs—but also two of the most damaging to the kidney owing to oxidative damage and severe inflammation.39-41 Researchers around the world have found that silymarin and its components reduce and often entirely prevent the kidney damage caused by these drugs.42-45

Silymarin’s ability to protect against the oxidative stress produced by potent drugs suggests that it may be useful in protecting against more subtle, chronic injury by free radicals, particularly those generated by chronic blood glucose elevations. German researchers, for instance, have found that silymarin could entirely prevent injury to renal cells incubated with elevated glucose concentrations while blocking production of oxidative stress markers.46

Silymarin’s protective power also extends to ischemia/reperfusion injury (restoration of blood supply following restriction of blood flow). Turkish researchers demonstrated that they could completely prevent visible and functional damage to kidney structures exposed to this kind of injury by pre-treating animals with silymarin.47,48 Studies such as these have huge implications for the general population, because they suggest that by maintaining optimal antioxidant function through supplementation, we may be able to prevent much (if not most) of the chronic oxidative damage to which our kidneys are exposed daily.

Resveratrol

The considerable advance in our understanding of the cyclical relationships between oxidative stress, endothelial dysfunction, inflammation, atherosclerosis, and chronic kidney disease points to resveratrol as an intervention in the chain of events that ultimately lead to renal failure.49

Italian researchers are among the leaders in resveratrol research, and early in this century one group published remarkable research demonstrating the impact of resveratrol on preserving kidney structure and function in rats exposed to ischemia/reperfusion injury.50,51

Japanese and Indian urologists followed that up in 2005 and 2006 with reports detailing the mechanisms by which resveratrol combats oxidative damage following reperfusion, markedly reducing kidney dysfunction.52-56 Overwhelming bacterial infections (sepsis) are a common cause of kidney failure in the intensive care unit and following surgery or trauma. Turkish physiologists demonstrated that resveratrol can reduce or prevent both kidney and lung injury in septic rats.57

Resveratrol’s unmatched antioxidant and anti-inflammatory potential has been tapped in studies of its ability to prevent drug-induced kidney damage as well. Nephrotoxicity in rats exposed to the antibiotic gentamicin was significantly reduced and more rapid healing of injured kidney tissue was attained using resveratrol, with dramatic reduction in markers of oxidant injury.58 A team of toxicologists in Brazil demonstrated its kidney protective power against cisplatin, the powerful chemotherapy agent responsible for so much drug-induced kidney damage.59 Finally, Indian pharmacologists were successful in protecting animal kidneys from damage caused by another common chemotherapy and immune suppressant drug cyclosporine A by pre-treating the animals with resveratrol.56

Since diabetes is the leading cause of kidney disease—and because the damage it inflicts is largely mediated by free radical production resulting from destructive alteration of proteins by glucose (glycation)—researchers have explored resveratrol as a preventive in diabetic kidney damage. Promising work has come from Indian pharmacologists, who’ve shown that they could significantly attenuate kidney damage in rats with experimentally induced diabetes—even 4 weeks after the diabetes was induced!60

In the researchers’ own words, “The present study reinforces the important role of oxidative stress in diabetic kidney disease and points towards the possible antioxidative mechanism being responsible for the renoprotective action of resveratrol.”

Resveratrol’s unmatched antioxidant and anti-inflammatory potential has been tapped in studies of its ability to prevent drug-induced kidney damage as well.

Lipoic Acid

Like resveratrol, lipoic acid is a powerful antioxidant with few known side effects.76 Lipoic acid has been successfully employed in the laboratory to block the oxidative damage caused by ischemia/reperfusion injury, thereby opening the door to another effective treatment for this common cause of acute kidney failure.77 For example, in 2008 researchers showed that they could reverse all adverse effects on renal function and lab abnormalities produced following experimental ischemia/reperfusion injury in animals.78

Lipoic acid has been comprehensively studied worldwide for its power to prevent or mitigate drug-induced kidney damage. We know that lipoic acid is an effective kidney-protective agent against damage inflicted by Adriamycin®,79,80 the immunosuppressive drug cyclosporine A,76,81,82 and even against acute toxic doses of the pain reliever acetaminophen.83 In studies of protection against cyclosporine toxicity, lipoic acid also helped to normalize blood lipid abnormalities.82

Nephrologists at Georgetown University are examining lipoic acid in the context of diabetic kidney disease. Their results show it can improve renal function in diabetes by lowering sugar levels.84

They have also recently demonstrated that lipoic acid lowers protein loss in urine and improves kidney structure and function in diabetic laboratory animals by reducing oxidative stress.84

In yet another compelling study, Korean researchers recently showed that they could improve kidney patients’ responses to the vasodilator (blood vessel relaxer) nitric oxide (NO) by supplementing them with lipoic acid.85 Loss of endothelial responsiveness to NO is a cause of vascular disease in diabetics, and a chemical called asymmetric dimethylarginine (ADMA) is a sensitive marker and predictor of cardiovascular outcome in patients with end-stage renal disease. Fifty patients on hemodialysis were treated with lipoic acid 600 mg per day for 12 weeks. Levels of the marker ADMA remained unchanged in the control group, but fell significantly in the lipoic acid group, suggesting that lipoic acid may reduce the risk of cardiovascular complications in this group of patients.

Risks to Kidney Health

Given the toxic, high-pressure conditions involved in renal function and the delicacy of the kidney’s structural components, it comes as no surprise that an array of near-constant internal and external insults may take a severe toll on the glomeruli and other parts of the kidney. Their incremental damage and destruction leads to the progressive decline in renal function seen in aging humans.

These internal and external insults include:

Hypertension. Over time, chronic high blood pressure inflicts damage to the endothelial cells lining the kidney’s blood vessels, including those within the glomeruli. The result is a familiar cascade of events that leads to the thickening of blood vessel walls and reduction in blood flow seen in atherosclerosis. Reduced blood flow is in turn directly translated into lower GFR. Pressure damage to the glomeruli also diminishes their filtration capacity, permitting large protein molecules such as albumin to pass into urine instead of remaining in circulation. (This is why urine albumin levels are used to detect kidney disease.)

Elevated serum glucose. Diabetes is now the leading cause of CKD.61 Experts predict even greater increases in CKD if rates of diabetes incidence continue to rise steeply.62 It should be noted, however, that high blood sugar poses a threat to kidney health even in non-diabetic individuals. Chronic exposure to glucose degrades and destroys kidney cells through the formation of advanced glycation end products (AGEs)—molecules generated through the pathologic binding of glucose to proteins in the body. AGEs cause primary structural proteins in the cells to cross-link and become non-functional, increasing oxidative stress, inflammation, and directly damaging kidney tissue.63-66 It has been established that even early-stage insulin resistance is associated with CKD.67

Excess fatty tissue. Body fat contributes to the development of CKD through production of inflammatory cytokines specific to adipose (fatty) tissue called adipokines. Along with AGEs and oxidative stress, adipokines exacerbate the inflammation commonly found in people with CKD.67 For this reason, metabolic syndrome—co-occurring insulin resistance, hypertension, and abdominal obesity—represents a perfect storm for the development of CKD. A 2007 study found that metabolic syndrome occurs in 30.5% of individuals with stage 4 or stage 5 chronic kidney disease.68 Metabolic syndrome increases the risk of chronic kidney disease, even before diabetes manifests.69

Protein over-consumption. Ingesting an excessive amount of protein, particularly meat, may tax the kidneys to the point of distress. The extraordinary increase in individuals adhering misguidedly to high-protein diets in order to lose weight has had the unintended consequence of boosting rates of kidney damage and disease. Meat consumption also results in high AGE production and the consequent inflammatory injury to kidney tissue.69 A prudent approach to dietary protein is thus encouraged by most experts, particularly in people who already have some degree of CKD.

Drugs. The nephrotoxic side effects of many commonly used medications comprise another significant causative factor in CKD. Chief among the mechanisms by which drugs cause kidney damage are oxidative stress and adverse alterations in cellular energy management. So-called “analgesic nephropathy” involves destruction of the active regions of the kidney by overuse of pain relievers, usually used in combinations of two or more, including the common over-the-counter medication acetaminophen (Tylenol®) as well as non-steroidal anti-inflammatory medications (NSAIDs) including high-dose aspirin, and ibuprofen (Advil®, Motrin®).70-73 Chemotherapy agents have also been shown to significantly impair renal function.74,75 Please note that acetaminophen inflicts kidney damage via a different mechanism than pain relieving drugs like ibuprofen.

Overcoming CKD-Induced Fatigue

L-carnitine, an amino acid-derived nutrient crucial to cellular energy management, can play a vital role in kidney disease prevention and management.86,87 Carnitine deficiency is itself a known causative factor in the development of kidney disease. Conversely, patients with kidney disease frequently develop carnitine deficiency, especially those on dialysis. Carnitine therapy is known to lead to improvements in many kidney-disease-associated complications including cardiovascular disease, anemia, decreased exercise tolerance, weakness, and fatigue.87

As noted earlier, CKD sufferers are at very high risk for developing cardiovascular complications, including heart attacks and heart failure. This is thought to be in part related to massive oxidative stress induced by kidney disease, and partly to inadequate energy management in cardiac tissues induced by carnitine deficiency.88 The frequent result of these interrelated factors is a massive deterioration in energy, exercise tolerance, quality of life—and perhaps even longevity.89

As early as 1998 scientists in Kentucky discovered that supplementation with L-carnitine could improve patient-reported general health, vitality, and physical function in people on dialysis.90 In 2001, research by clinicians at Los Angeles Medical Center showed that L-carnitine, given intravenously to dialysis patients, could reduce fatigue and preserve exercise capacity.91 A literature review by nephrologists at Vanderbilt University in 2003 indicated that L-carnitine supplementation should be used to improve red blood cell count in dialysis patients whose anemia doesn’t respond to therapy with the hormone erythropoietin.92 Finally, more data from Italy demonstrate that L-carnitine supplements can help suppress levels of the inflammatory marker C-reactive protein, potentially reducing cardiovascular risk in dialysis patients.93

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